Mitochondrial Haplogroup T Is Associated with Obesity in Austrian Juveniles and Adults

<div><p>Background</p><p>Recent publications have reported contradictory data regarding mitochondrial DNA (mtDNA) variation and its association with body mass index. The aim of the present study was to compare the frequencies of mtDNA haplogroups as well as control region (CR) polymorphisms of obese juveniles (n = 248) and obese adults (n = 1003) versus normal weight controls (n_juvenile = 266, n_adults = 595) in a well-defined, ethnically homogenous, age-matched comparative cohort of Austrian Caucasians.</p><p>Methodology and Principal Findings</p><p>Using SNP analysis and DNA sequencing, we identified the nine major European mitochondrial haplogroups and CR polymorphisms. Of these, only the T haplogroup frequency was increased in the juvenile obese cohort versus the control subjects [11.7% in obese vs. 6.4% in controls], although statistical significance was lost after adjustment for sex and age. Similar data were observed in a local adult cohort, in which haplogroup T was found at a significantly higher frequency in the overweight and obese subjects than in the normal weight group [9.7% vs. 6.2%, p = 0.012, adjusted for sex and age]. When all obese subjects were considered together, the difference in the frequency of haplogroup T was even more clearly seen [10.1% vs. 6.3%, p = 0.002, OR (95% CI) 1.71 (1.2–2.4), adjusted for sex and age]. The frequencies of the T haplogroup-linked CR polymorphisms C16294T and the C16296T were found to be elevated in both the juvenile and the adult obese cohort compared to the controls. Nevertheless, no mtDNA haplogroup or CR polymorphism was robustly associated with any of several investigated metabolic and cardiovascular parameters (e.g., blood pressure, blood glucose concentration, triglycerides, cholesterol) in all obese subjects.</p><p>Conclusions and Significance</p><p>By investigation of this large ethnically and geographically homogenous cohort of Middle European Caucasians, only mtDNA haplogroup T was identified as an obesity risk factor.</p></div

Linear model results on the 24 selected SNPs in the SAPHIR, KORA F3 and CoLaus study using an additive genetic model, adjusted for age, sex and BMI, as well as the combined fixed effects meta-analysis results.

<p>Effect estimates and standard errors (for the combined as well as sex-specific analyses) are based on the original adiponectin scale, whereas p-values are taken from the linear regression on log(adiponectin).</p

Characteristics of the 24 SNPs in SAPHIR, KORA F3 and CoLaus, including genotype quality (call rate or imputation quality RSQR).

*<p>Minor and Major alleles based on the plus-strand.</p>**<p>Number of homozygotes for the major allele/heterozygotes/homozygotes for the rare allele; For KORA F3 and CoLaus, where imputed genotype scores have been used, this are the numbers of the “best guess” genotypes (KORA F3) and rounded sum of genotype scores.</p>***<p>Based on exact test of Hardy-Weinberg Equilibrium (HWE).</p

Linkage disequilibrium structure across the <i>SREBF1</i> single nucleotide polymorphisms.

<p>The pair wise linkage disequilibrium (R² and D’) is given for each pair of single nucleotide polymorphisms. Color-coding is based on R². The diagonal line indicates the physical position of the single nucleotide polymorphisms relative to each other.</p

Clinical characteristics of the subjects from SAPHIR, KORA F3 and CoLaus studies (means ± SD or numbers (%)), for whom all relevant variables and genotypes are available.

<p>Clinical characteristics of the subjects from SAPHIR, KORA F3 and CoLaus studies (means ± SD or numbers (%)), for whom all relevant variables and genotypes are available.</p

Schematic structure of <i>SREBF1</i> gene.

<p>Exons are numbered indicating the alternatively spliced -a and -c variants. Genomic location of the analyzed single nucleotide polymorphisms are marked. The single nucleotide polymorphisms highlighted in yellow showed a strongly associated with adiponectin levels in our study. The single nucleotide polymorphism highlighted in grey showed a significant association in a previous study <a href="http://www.plosone.org/article/info:doi/10.1371/journal.pone.0052497#pone.0052497-Felder1" target="_blank">[26]</a> and was only borderline significantly associated in the present study (p = 0.004).</p

Results of linear mixed models and linear models on the investigated lipid phenotypes for all STRs which are significantly associated with lipids in KORA F4 and SAPHIR combined: 1) regression of the sum of STR alleles on lipids in KORA F4 and SAPHIR combined, 2) regression of the sum of STR alleles on lipids in SAPHIR, 3) regression of the sum of STR alleles on lipids in KORA F4, 4) regression of the minor allele using the lead SNP (LS) in the gene region on lipids in KORA F4, 5) regression of the minor allele using the best SNP in the gene region (LS+/−100 kB) on lipids in KORA F4.

<p>All analyses are adjusted for age and sex.</p>a<p>according to Teslovich et al. <a href="http://www.plosone.org/article/info:doi/10.1371/journal.pone.0102113#pone.0102113-Teslovich1" target="_blank">[1]</a>; beta effect estimate for the lead SNP refers to the minor allele, assuming an additive model.</p

Frequencies (%) of CR polymorphisms higher than 5% in either overweight and obese or normal weight adults (both SAPHIR cohort) and odds ratios (OR) for the association between genetic variation and disease state.

<p>¹n: number of individuals with the respective polymorphism.</p><p>2 p-value: derived from Mann-Whitney-U test.</p><p>3 OR: Odds Ratio</p><p>4 CI: Confidence Interval</p><p>5 adjusted for sex and age</p><p>Frequencies (%) of CR polymorphisms higher than 5% in either overweight and obese or normal weight adults (both SAPHIR cohort) and odds ratios (OR) for the association between genetic variation and disease state.</p

Frequencies (%) of Caucasian mitochondrial haplogroups in juvenile obesity cases and controls.

<p>n¹ = Number of individuals with respective mtDNA haplogroup.</p><p>2Haplogroups that could not be assigned to one of the nine major European haplogroups by the SNP combination.</p><p>3Juvenile obese cohort 1</p><p>⁴Juvenile control cohort</p><p>Frequencies (%) of Caucasian mitochondrial haplogroups in juvenile obesity cases and controls.</p

Characteristics of the study populations.

<p>1 SD: standard deviation</p><p>2 Juvenile obese cohort 1</p><p>3 Juvenile control cohort</p><p>4 Adult cohort</p><p>Characteristics of the study populations.</p